In the course of periodontal disease, infection of gingival tissue by plaque bacteria causes the ligaments attaching the gum and teeth to recede, decalcifies the bony structure holding the teeth roots to the bone, and forms periodontal pockets in the gingival tissue adjacent the teeth. Successful periodontal restoration is known to occur if periodontal ligament cells are allowed to colonize root surfaces preferentially over gingival epithelial cells, gingival fibroblasts or osteoblasts. Surgery alone, however, does not result in restoration of lost periodontium.
In an attempt to promote and achieve periodontal restoration, implant techniques have been developed. For example, microporous membranes, such as the Millipore(copyright) filter and GORE-TEX(copyright) membranes, have been developed for use in periodontal tissue regeneration. Typically, the periodontal flap is cut, and the microporous membrane is surgically inserted to cover the surface of the tooth root and to physically occlude epithelial cells from apically migrating along the root surface.
These membranes have several drawbacks. Besides providing variable results, a second surgical entry is needed to remove the membrane after tissue regeneration has been achieved because the membranes are not biodegradable. There is also a higher incidence of infection in connection with their use.
To preclude surgical removal of an implant, membranes made of bioabsorbable material, such as microfibrillar collagen, polylactic acid, and polygalactin (Vicryl(copyright)) mesh have been used. Fitting and positioning these membranes to the implant site is cumbersome and time-consuming, and the therapeutic effect of these membranes has been unpredictable. In addition, the degradation time of membranes composed of collagen has been variable, and the risk of adverse immunological reaction to this foreign protein material in the body presents a major concern.
A liquid system containing a biodegradable polymer has been developed wherein the solution is injected into an implant site, and solidifies in situ to form a biodegradable implant having a solid microporous matrix. Advantageously, the implant does not require surgical removal. However, controlled delivery and containment of a liquid system within a particular area within the implant site is difficult, and the liquid may spread to areas other than the implant site.
Therefore, there is a need for an article which will facilitate the controlled placement in an implant site of a liquid polymer solution for forming an implant. A further need is to develop a precursor to a solid implant which is neither all-liquid nor all-solid but will solidify in situ to form a solid microporous implant. There is also a need for a precursor to a solid implant that can be applied to a tissue defect in an animal and shaped or molded in situ to conform to the defect. Yet another need is to develop in vivo and ex vivo methods of making an implant precursor having such characteristics.
These and other goals are achieved by the present invention which is directed to an implant precursor for implantation in an animal, such as a human or other mammal, which will eventually harden in situ to a solid implant having a microporous matrix. The invention also provides a method of making and using the implant precursor. An apparatus is also provided for forming an implant precursor ex vivo, and a kit containing the apparatus.
The implant precursor is a two-part structure composed of an outer sac with a liquid content. The implant precursor is composed of a biocompatible, biodegradable and/or bioerodible, water-coagulable thermoplastic polymer or copolymer which is substantially insoluble in an aqueous media, and a pharmaceutically-acceptable, water-soluble organic solvent. The two-part structure of the implant precursor is formed by contacting a portion of a water-coagulable polymer solution with water or other aqueous medium, whereupon the solvent dissipates into the aqueous medium. This causes the polymer on the surface of the portion of polymer solution adjacent the aqueous medium to coagulate to form an outer sac having a firm consistency ranging from gelatinous to waxen-like, while the solution inside the sac (i.e., sac contents) remains a liquid. The sac contents of the implant precursor may range in consistency from watery to slightly viscous.
The implant precursor may-be applied to an implant site in an animal, such as a void, a defect, surgical incision, and the like, in or on a hard or soft tissue. Once placed in the implant site, the implant precursor eventually forms a solid microporous implant by the dissipation of the organic solvent into surrounding tissue fluids and the further coagulation of the polymer. Preferably, the matrix of the resulting implant has a two-layered pore structure with a highly porous inner core portion and a comparatively less porous outer surface layer or skin. Pores are formed in the solid matrix of the implant by dissipation of the solvent out of the composition into surrounding tissue fluids. Optionally, the implant precursor may include a separate pore-forming agent that is capable of generating pores within the polymer matrix of the solid implant, as for example, sucrose, sodium chloride, a cellulose-based polymer, and the like.
The resulting solid implant is biodegradable, bioabsorbable, and/or bioerodible, and will be gradually absorbed into the surrounding tissue fluids, as for example, blood serum, lymph, cerebral spinal fluid (CSF), saliva, and the like, and become disintegrated through enzymatic, chemical or cellular hydrolytic action. Generally, the implant will be absorbed over a period of up to about 2 years to about 3 years, preferably within about 1-9 months, preferably within about 60-180 days. The implant may be used, for example, for selective enhancement of cell growth and tissue regeneration, delivery of biologically-active substances to the animal, and the like.
The implant precursor may also include a biologically-active agent, or bioactive agent, as for example, an anti-inflammatory agent, an antiviral agent, an antibacterial or antifungal agent useful for treating and preventing infections in the implant site, a growth factor, a hormone, and the like. The implant resulting from the in situ coagulation of the implant precursor, may then serve as a system for delivering the biologically-active agent to the animal.
A release rate modification agent may also be included in the implant precursor for controlling the rate of breakdown of the implant matrix and/or the rate of release of a bioactive agent in vivo from the implant matrix. Examples of suitable substances for inclusion as a release rate modification agent include dimethyl citrate, triethyl citrate, ethyl-heptanoate, glycerin, hexanediol, and the like.
The invention also includes a method of making the implant precursor. The implant precursor may be formed in vivo or ex vivo by (a) coating the surface of a suitable support substrate with an effective amount of an aqueous medium to form a layer; (b) dispensing onto the aqueous layer, an effective amount of a liquid polymer solution made of a water-coagulable, biodegradable thermoplastic polymer such as polylactide, polycaprolactone, polyglycolide, or copolymer thereof, and a water-soluble, pharmaceutically-acceptable organic solvent such as N-methyl-2-pyrrolidone; (c) applying an effective amount of an aqueous medium onto the surface of the polymer solution; and (d) allowing the polymer adjacent the aqueous medium to coagulate to form the implant precursor having an outer sac with a liquid content. Preferably, the thickness of the implant precursor is controlled, for example, by compressing the coagulating polymer mass between two solid flat surfaces such as a glass plate, porous plastic, and the like. The aqueous medium is applied onto the surface of the support substrate and the surface of the polymer solution in a minor but effective amount to initiate coagulation of the polymer to form the outer sac of the implant precursor.
The implant precursor may be formed in vivo by dispensing the polymer solution onto a soft or hard tissue or other support substrate in the body of an animal. The precursor may also be formed ex vivo by dispensing the polymer solution onto a support substrate made, for example, from glass, a porous plastic, sintered stainless steel, porcelain, bone material, and other like materials.
In a variation of forming an implant precursor, an amount of the foregoing liquid polymer solution is applied to the surface of the support substrate to form a line which delineates a boundary around a defined area. The implant precursor may then be formed within the confines of the boundary line area. When the foregoing boundary line is formed on a tissue defect in vivo, an implant precursor may be prepared outside the body and applied to the defect within the confines of the boundary line.
Optionally, a support layer may be applied to the tissue surface to provide an adhesive substrate for securing the implant precursor onto the surface of the tissue defect. Useful substances for forming an adhesive support layer include, for example, the foregoing liquid polymer solution, a water-soluble substance such as gelatin, and the like. The support layer may be in the form of a bead, a film or coating, and the like, having a thickness as desired.
The invention also includes an apparatus for forming an implant precursor ex vivo. The apparatus is preferably a two-part assembly comprising support means for maintaining the polymer solution on a surface during formation of an implant precursor such as a porous plate or block, and means for compressing the polymer solution during formation of the implant precursor. Preferably, the support means and compressing means are connected together by hinging means positioned along one edge of the support means and the compressing means, such that the compressing means may be pivoted and placed onto the polymer solution on the support means. The support means and/or compressing means are preferably made of a porous material, as for example, a porous plastic, sintered stainless steel, porcelain, and other like materials which are absorptive to water. An aqueous medium is applied as a layer over the surface of the support means, the polymer solution applied over the aqueous layer, and a second aqueous layer is applied over the polymer solution. Preferably, two or more spacers such as a washer, are arranged on the surface of the support means to form a defined area thereinbetween, and the implant precursor is formed on the area between the spacers. The compressing means is then positioned over the support means with the spacers and coagulating polymer solution sandwiched thereinbetween, preferably compressing the coagulating polymer mass. The support means and compressing means of the apparatus are maintained in a sandwich arrangement until the outer sac of the implant precursor is formed. The support means and compressing means are then separated and the resulting implant precursor is removed from the apparatus, trimmed as desired, and placed into the implant site.
Also provided is a kit containing, in combination, the precursor-forming apparatus, one or more barrier means, an amount of the aforedescribed polymer solution in one or more vials or other containers, and an amount of an aqueous medium preferably a phosphate buffered saline in one or more vials or other like container. The kit may also include a tweezers or other like means for picking up the formed implant precursor; a calibrated tweezers or other like means for measuring the dimensions of the tissue defect and/or the implant precursor; a gridded template or other like means for measuring the dimensions of the implant precursor; a scalpel, razor or other like means for trimming the implant precursor to a desired size; and/or a cotton pad or other like means for blotting the aqueous medium from the surface of the implant precursor.
The invention also includes a method for treating a tissue defect in an animal. The implant precursor may be used, for example, for enhancing cell growth and tissue regeneration, wound and organ repair, nerve regeneration, soft and hard tissue regeneration, and the like. According to the invention, the foregoing implant precursor is applied to the tissue defect and allowed to coagulate to an implant having a solid microporous matrix.
As used herein, the term xe2x80x9cimplant sitexe2x80x9d is meant to include a site, in or on which the implant precursor is formed or applied, as for example, a soft tissue such as muscle or fat, or a hard tissue such as bone. Examples of implant sites include a tissue defect such as a tissue regeneration site; a void space such as a periodontal pocket, surgical incision or other formed pocket or cavity; a natural cavity such as the oral, vaginal, rectal or nasal cavities, the cul-de-sac of the eye, and the like; and other sites into which the implant precursor may be placed and formed into a solid implant. The term xe2x80x9cbiodegradablexe2x80x9d means that the polymer and/or polymer matrix of the implant will degrade over time by the action of enzymes, by hydrolytic action and/or by other similar mechanisms in the human body. By xe2x80x9cbioerodible,xe2x80x9d it is meant that the implant matrix will erode or degrade over time due, at least in part, to contact with substances found in the surrounding tissue fluids, cellular action, and the like. By xe2x80x9cbioabsorbable,xe2x80x9d it is meant that the polymer matrix will be broken down and absorbed within the human body, for example, by a cell, a tissue, and the like
Since the implant precursor does not flow like a liquid, it provides easy manipulation and placement of a liquid polymer system for forming an implant on a select area of a tissue defect without the uncontrolled flow of the polymer solution outside the area of the implant site. The present implant precursor provides a system for forming an implant with a desired thickness, size, and shape. Unlike a solid implant, the implant precursor is easy to manipulate and may be shaped and molded within the defect site as it solidifies. Advantageously, the moldability of the implant precursor allows it to conform to irregularities, crevices, cracks, holes, and the like, in the tissue defect site. In addition, the surface of the implant precursor is tacky to the touch and tends to remain in place where it is applied to a tissue defect.